PMID- 36341808
OWN - NLM
STAT- MEDLINE
DCOM- 20221122
LR  - 20221224
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 222
DP  - 2023 Jan 1
TI  - Fear extinction induced by activation of PKA ameliorates anxiety-like behavior in 
      PTSD mice.
PG  - 109306
LID - S0028-3908(22)00365-3 [pii]
LID - 10.1016/j.neuropharm.2022.109306 [doi]
AB  - Prolonged exposure (PE) therapy aiming to promote fear extinction is a useful 
      treatment for post-traumatic stress disorder (PTSD). However, the mechanisms 
      underlying fear extinction and effective methods used to promote fear extinction 
      in PTSD are still lacking. In this study, we displayed dysfunctions of cyclic 
      adenosine 3,5-monophosphate (cAMP)-protein kinase A (PKA), protein kinase B 
      (Akt)/mammalian target of rapamycin (mTOR) and calcium signaling in peripheral 
      serum of PTSD patients using bioinformatics analysis. Later, we confirmed the 
      dysfunctions of cAMP-PKA, AKT/mTOR and calcium signaling in the hippocampus of 
      PTSD mice. Moreover, the reduction of calpain1 in the hippocampus enhanced fear 
      memory acquisition. Single activation of PKA by systemic application of rolipram 
      (ROL) or meglumine cyclic adenylate (M-cAMP) before re-exposure promoted fear 
      extinction and improved anxiety-like behavior in PTSD mice. Moreover, systemic 
      application of ROL before re-exposure improved hippocampal brain-derived 
      neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling and 
      calpain1/AKT/mTOR signaling. Interestingly, the effects of activation of PKA 
      could be partially blocked by TrkB antagonist, ANA-12 and mTOR inhibitor, RAPA. 
      Finally, intranasal administration of ROL could also adjust the abnormality of 
      fear memory and improve anxiety-like behaviors in PTSD mice. Collectively, 
      activation of PKA could promote fear extinction, which correlated with the 
      reduction of anxiety-like behavior. The mechanisms were related to the BDNF/TrkB 
      and calpain1/AKT/mTOR signaling pathways. PKA activation might be a useful 
      complementary therapy for PE in the symptom elimination of PTSD.
CI  - Copyright (c) 2022 Elsevier Ltd. All rights reserved.
FAU - Gao, Feng
AU  - Gao F
AD  - Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory 
      of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, 
      Hefei, 230012, China.
FAU - Wang, Juan
AU  - Wang J
AD  - Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory 
      of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, 
      Hefei, 230012, China.
FAU - Yang, Shaojie
AU  - Yang S
AD  - Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory 
      of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, 
      Hefei, 230012, China.
FAU - Ji, Manman
AU  - Ji M
AD  - Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory 
      of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, 
      Hefei, 230012, China.
FAU - Zhu, Guoqi
AU  - Zhu G
AD  - Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory 
      of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, 
      Hefei, 230012, China. Electronic address: guoqizhu@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221029
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - K676NL63N7 (Rolipram)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Fear
MH  - *Stress Disorders, Post-Traumatic/drug therapy
MH  - Cyclic AMP-Dependent Protein Kinases
MH  - Proto-Oncogene Proteins c-akt
MH  - Brain-Derived Neurotrophic Factor
MH  - Extinction, Psychological
MH  - Anxiety/drug therapy
MH  - TOR Serine-Threonine Kinases
MH  - Rolipram
MH  - Calcium Signaling
MH  - Adenosine
MH  - Mammals
OTO - NOTNLM
OT  - Fear extinction
OT  - PKA
OT  - PTSD
OT  - Prolonged exposure
OT  - Synaptic plasticity
OT  - calpain1
COIS- Declaration of competing interest The authors declare that there is no conflict 
      of interest associated with the manuscript.
EDAT- 2022/11/08 06:00
MHDA- 2022/11/23 06:00
CRDT- 2022/11/07 06:17
PHST- 2022/08/15 00:00 [received]
PHST- 2022/10/18 00:00 [revised]
PHST- 2022/10/23 00:00 [accepted]
PHST- 2022/11/08 06:00 [pubmed]
PHST- 2022/11/23 06:00 [medline]
PHST- 2022/11/07 06:17 [entrez]
AID - S0028-3908(22)00365-3 [pii]
AID - 10.1016/j.neuropharm.2022.109306 [doi]
PST - ppublish
SO  - Neuropharmacology. 2023 Jan 1;222:109306. doi: 10.1016/j.neuropharm.2022.109306. 
      Epub 2022 Oct 29.